Accumulation of poly(ADP-ribose) polymerase inhibitors in children with chronic renal failure
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Nicotinamide, N-methyl-2-pyridone-5-carboxamide (Met2PY) and N-methyl-4-pyridone-3-carboxamide (Met4PY) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide (NAD) that can potentially inhibit poly(ADP-ribose) polymerase 1 (PARP-1; DNA repair enzyme). Our research was aimed at establishing whether chronic renal failure (CRF) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit PARP-1 activity. Nicotinamide, Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children. The effect of these NAD metabolites on PARP-1 activity was studied in vitro. We found that plasma concentration of all NAD metabolites (nicotinamide, Met2PY, Met4PY) in children with CRF could reach the concentration of 2, 30 and 10 μM as compared to 0.2, 1 and 0.5 μM, respectively, in healthy children. The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF. We found that Met2PY, Met4PY and nicotinamide inhibited in vitro PARP-1 activity with IC50 values of 2.1, 0.18 and 0.12 mM, respectively. Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of PARP-1 activity. NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults.
KeywordsPARP-1 NAD metabolism Nicotinamide Met2PY Met4PY Chronic renal failure
This work was supported by grants from the Ministry of Science and Information Society Technologies of Poland (3 PO5B 118 25 and PBZ-KBN-101/T09/2003/17). Part of this paper was presented at the International Congress on Uremic Toxicity, held in Würzburg (13–16 September 2002) and published in abstract form.
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